qt overview pe - uct.ac.za
TRANSCRIPT
The QT Interval– Safety Endpoint for DR-‐TB trials
Kelly Dooley & Gary Maartens(Disclaimer: I know very little cardiac electrophysiology)
The ECG tracing
Physiology of a cardiac myocyte
• Resting state: Inside of cell membrane negatively charged, outside of cell membrane positively charged• Depolarization: Inside of cell membrane becomes positively charged relative to outside of cell membrane• Repolarization: Return to resting state• Excitability: electrical impulse starts at one end of cardiac cell, rapidly propagates to the other end• Conductivity: cardiac cell transfers impulse to neighboring cell
Flow of ions (Na+, Ca2+, K+) across the cell membrane constitutes a flow of electricity
How to quickly and accurately master ECG interpretation, Dale Davis
The QT interval represents Ventricular depolarization and repolarization
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Resting state-‐ “polarized”-‐ -‐ + + + + + + + + + +
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Depolarization beginning
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Repolarization beginning-‐ -‐ -‐ -‐ -‐ -‐ -‐ -‐ -‐ -‐ -‐ -‐ -‐ + + ++ + + + + + + + + + -‐ -‐ -‐
http://www.frontiersin.org/files/Articles/72177/fped-‐01-‐00039-‐HTML/image_m/fped-‐01-‐00039-‐g001.jpg
http://journal.frontiersin.org/article/10.3389/fphar.2010.00137/full
Why care about the QT interval?
Torsades de Pointes:“twisting of the spikes”Life-‐threatening
Things that prolong the QT interval
• Electrolyte Abnormalities especially Magnesium and Potassium (often reduced by aminoglycosides) • Bradycardia/ Sino Atrial Blocks• Myocardial Ischemia/Infarction• Congestive Heart Failure, Hypoxia• Central nervous system disorders• Endocrinopathy: Hypothyroidism (often caused by ethionamide/PAS)• Congenital Long QT Syndrome• Drugs
QT as a surrogate for risk of torsades
QT prolongation is a poor surrogate for torsades, but all drugs that produce torsades prolong QT
Torsades is rare• Terfenadine – incidence of torsade 1/50,000• Unacceptable for a medicine for hay fever
• Quinidine – incidence of torsade 1-‐2%
Drug-‐induced Torsades
Susceptible host (prolonged QT due to cardiac disease, long QT, etc)
Multiple QT-‐prolonging drugs e.g.:• Bedaquiline• Clofazimine
• Delamanid
• Moxifloxacin
• Efavirenz
QT-‐prolonging drug with drug that inhibits its metabolism
How do drugs prolong the QT interval?
• Direct blocking of Ikr channel (HERG)
• Indirectly, by effects on surface expression of the ion channel
• May affect trafficking of other ion channels
• 40% of direct hERG blockers also have effects on hERGtrafficking
Pre-‐clinical QT Safety Studies
Screens:In vivo HERG studiesAnimal models
How relevant are pre-‐clinical QT studies?Effects in vitro may not be seen in vivo & vice versaMetabolites may vary significantly between animals and humans (e.g. metabolites of bedaquiline & delamanid drive QT effects)Animal models don’t reliably predict human effects
Clinical: ICH E14 TET (Thorough ECG Trial)• All new drugs with systemic bioavailability should have a thorough QTc/QT trial
performed irrespective of preclinical profile• The trial needs to define a 5 ms effect with a one sided 95% CI that excludes a
10 ms effect using time matched methodsThe exception: Drugs that cannot be given to healthy subjects
Design:• Normal healthy subjects• Typically 4 arms: placebo, therapeutic dose, supratherapeutic dose, active comparator (moxifloxacin)• Can be cross-‐over or parallel design, depending on drug characteristics
Typical paces drug is put through to assess cardiac risk
Thorough QT study -‐ soon to be replaced?
Cardiac Safety Research Consortium (CSRC) study, CPT 97: 326
QT study mirrors PK: 400 vs 800 mg Moxifloxacin
Baseline-‐ and placebo-‐controlled changes in QTcF with MOX 400 mg (•) and MOX 800 mg (o)
Plasma concentrations of MOX when given at a dose of 400 mg (•) and 800 mg (o)
Moon et al. Drugs RD (2014) 14: 63
E14 Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential for Non-‐Antiarrhythmic Drugs
“In clinical trials, a prolongation of QTc > 500 ms during therapy has been a threshold of particular concern.”
What magnitude of QTc prolongation is dangerous?
Measuring the QT
Machine vs. manual measurement• Artefact, end of T wave
Correction factors• As heart rate increases, QT must shorten to allow for next beat• Fridericia’s correction (QTcF):• QTcF = QT/3√RR• Note RR= 60/heart rate
• Bazett’s correction (QTcB) not recommended:• QTcB overcorrects at high heart ratesà false impression of a large QTc increase
http://a-‐fib.com/wp-‐content/uploads/2012/08/Schematic-‐diagram-‐of-‐normal-‐sinus-‐rhythm-‐for-‐a-‐human-‐heart-‐as-‐seen-‐on-‐ECG-‐Wikipedia-‐free-‐to-‐use.png
Central reading is essential
Heart Rhythm Vol. 2 June 2005
Prolonged BDQ, QTc change over time: observational n=43; 11 QTcF >500 ms
Eur Respir J 2017; 49: 1601799
BDQ QTc change over time RCT, central read
Eur Resp J 2016;47:564N=228
QT variability
• Normal QTc: <450 in men, <470 in women
• QTc variation in an individual is expected (up to 75 msduring 24 hours)
• Difficult to tell if changes in QTc are drug related or are due to usual QTc variation with time
• Sources of variability• Sex (Females have longer QTs)• Age (QT increases with age)• Heart rate• Position• Autonomic tone• Meals• Menstrual cycle• Time of day• Illness• Technical Issues
Get replicate ECGs!
Practical points for QT study design
• ECGs done in triplicate, resting, 5-‐10 minutes apart• Ideally do ECGs at similar time of day, approximating Tmax• Sites must read ECGs & react to their interpretation of grade 3/4 QTc prolongation, but central reads recorded for database – training of site clinicians important• SOP for grade 3/4 QTc should include measuring K & Mg, with aggressive replacement if low• List of RELEVANT QT prolonging concomitant meds (CredibleMeds.org)
https://www.crediblemeds.org/